There have been many studies of the effects of tobacco smoke on human health. There also have been many efforts to determine which of the thousands of components of tobacco smoke have deleterious properties. It remains controversial as to which tobacco components have deleterious health effects, and whether any single tobacco smoke component causes specific health problems. It has recently been established, however, that components of the combustion products of tobacco become covalently attached to proteins that are exposed to tobacco smoke. Further, these tobacco combustion product-derived adducts exhibit physico/chemical properties typical of advanced glycosylation endproducts (or AGEs), which glycation products are the familiar result of the Maillard reaction between proteins and reducing sugars. Moreover, a link between the accumulation of AGEs in vivo and various pathogenic processes with detrimental health consequences has been well established.
Although a sequence of non-enzymatic reactions between proteins and reducing sugars (such as glucose) has been recognized for many years, the biological and physiological consequences of such reactions and the products of this reaction sequence are still under investigation. The earliest recognized manifestation of non-enzymatic protein glycosylation (or glycation) was the appearance of brown pigments during long-term storage or cooking of food. This non-enzymatic browning reaction was identified by Maillard in 1912. Maillard observed that glucose or other reducing sugars react spontaneously with amino-containing compounds, such as amino acids and peptides, to form initial Schiff base adducts which can rearrange to generate the Amadori and Heyns products. These initial condensation products then undergo a series of additional spontaneous dehydrations, rearrangements and other reactions to form more advanced glycosylation endproducts, or AGEs. This reaction sequence has come to be known alternatively as the Maillard reaction, non-enzymatic browning, advanced glycosylation or glycation.
As a class, AGEs formed through the Maillard reaction are yellow/brown in color, exhibit a characteristic absorption/emission profile, have protein cross-linking activity, share immunological determinants, and have deleterious consequences as they accumulate in vivo.
The non-enzymatic rearrangement of the initial Schiff base formed by addition of glucose to a free amino group on a protein forms a stable amino, 1-deoxy ketosyl adduct known as an Amadori product. A parallel reaction involving a reducing ketose rather than an aldose generates an early glycation product known as the Heyns rearrangement product. Accumulation of these early glycation adducts can occur, for instance, with hemoglobin wherein rearrangement of the amino terminus of the .beta.-chain follows an initial reaction with glucose to form hemoglobin A.sub.1c, an important marker of glucose control in diabetes. Glycation reactions have also been found to occur with other body proteins, such as lens crystallins, collagen nerve proteins, and low density lipoproteins, as well as with DNA and aminophospholipids.
The Maillard browning process generates a diverse array of AGEs, each species of which occurs in low abundance. This diversity has complicated the identification and structural determination of specific AGEs. U.S. Pat. No. 4,665,192 identifies the fluorescent chromophore known as FFI, and a few other AGEs, such as AFGP (U.S. Pat. No. 5,017,696), pyrraline (Hayase et al., J. Biol. Chem. 263:3757-3764, 1989), and pentosidine (Sell and Monnier, J. Biol. Chem. 264:21597-21602, 1989) have also been identified.
Maillard reaction products have been shown to underlie a wide variety of both normal and pathogenic activities and responses that occur as AGEs accumulate on proteins in vivo. In addition, the non-enzymatic glycosylation of other biomolecules, such as the formation of AGEs on lipids and on lipid-containing particles, may also contribute to pathogenesis. Such lipid-AGEs, for instance, are thought to play a pathogenic role in atherogenesis, where formation of lipid-laden foam cells marks the initiation of atherosclerotic plaques. Glycation and oxidation of protein and lipid components of low-density lipoprotein (LDL) results in a loss of recognition of the apo B component by cellular LDL receptors, prolonging the circulating half-life of AGE-modified LDL and resulting in a preferential uptake of modified LDL, such as AGE-LDL and oxidized LDL , by "scavenger receptors," by AGE receptors and by other specialized cellular mechanisms. The enhanced endocytosis of modified LDL by vascular wall macrophages has been linked to their transformation into lipid-laden foam cells that characterize early atherosclerotic lesions. Other studies have demonstrated that AGE formation on DNA has mutagenic consequences.
U.S. patent application Ser. No. 08,772,335 filed Dec. 23, 1996, the disclosure of which is incorporated by reference herein, shows that exposure of proteins to tobacco extracts or to tobacco smoke or to extracts of tobacco combustion products leads to the accumulation on the proteins of covalently attached adducts. As a group, these tobacco- and tobacco smoke-derived adducts exhibit a physico/chemical profile that suggests significant structural overlap with the AGEs of the Maillard reaction. Like glycation-derived AGEs, tobacco- and tobacco smoke-derived adducts, as a group:
(a) are yellow/brown in color; PA1 (b) exhibit a characteristic absorption/emission profile (fluorescence at 440 nm upon excitation at 370 nm); PA1 (c) have protein cross-linking activity; and, PA1 (d) share immunological cross-reactivity with antibodies raised against and specific for AGEs formed by the Maillard reaction.
Furthermore, tobacco smokers and animals experimentally exposed to tobacco smoke accumulate adducts with the above physico/chemical characteristics of glycation-derived AGEs. Therefore, there is a need in the art to find compounds that can inhibit or prevent, in the users of tobacco or in those otherwise exposed to tobacco smoke, the accumulation of AGEs or AGE-like tobacco- or tobacco smoke-derived adducts.
Although the Ser. No. 08,772,335 patent application provides a limited number of agents to inhibit the accumulation of AGEs in persons exposed to tobacco smoke, there is a further need in the art to find additional products that can inhibit the accumulation of AGEs and/or AGE-like tobacco- or tobacco smoke-derived adducts in persons exposed to tobacco smoke, and in particular to provide such alternative products that are more effective inhibitors or exhibit fewer undesired side-effects than the agents of the Ser. No. 08,772,335 application.